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Transplant Toxicities

Low-dose irradiation prior to bone marrow transplantation results in ATM activation and increased lethality in Atm-deficient mice

Bone Marrow Transplantation volume 51, pages 560–567 (2016)Cite this article

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A Corrigendum to this article was published on 06 April 2016

This article has been updated

Abstract

Ataxia telangiectasia is a genetic instability syndrome characterized by neurodegeneration, immunodeficiency, severe bronchial complications, hypersensitivity to radiotherapy and an elevated risk of malignancies. Repopulation with ATM-competent bone marrow-derived cells (BMDCs) significantly prolonged the lifespan and improved the phenotype of Atm-deficient mice. The aim of the present study was to promote BMDC engraftment after bone marrow transplantation using low-dose irradiation (IR) as a co-conditioning strategy. Atm-deficient mice were transplanted with green fluorescent protein-expressing, ATM-positive BMDCs using a clinically relevant non-myeloablative host-conditioning regimen together with TBI (0.2–2.0 Gy). IR significantly improved the engraftment of BMDCs into the bone marrow, blood, spleen and lung in a dose-dependent manner, but not into the cerebellum. However, with increasing doses, IR lethality increased even after low-dose IR. Analysis of the bronchoalveolar lavage fluid and lung histochemistry revealed a significant enhancement in the number of inflammatory cells and oxidative damage. A delay in the resolution of γ-H2AX-expression points to an insufficient double-strand break repair capacity following IR with 0.5 Gy in Atm-deficient splenocytes. Our results demonstrate that even low-dose IR results in ATM activation. In the absence of ATM, low-dose IR leads to increased inflammation, oxidative stress and lethality in the Atm-deficient mouse model.

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  • 06 April 2015

    This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication

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Acknowledgements

We would like to thank Katrin Krug and Heike Korff for her technical assistance. The authors would also like to acknowledge support from a Loewe grant (LOEWE Center for Cell and Gene Therapy Frankfurt funded by Hessisches Ministerium für Wissenschaft und Kunst (HMWK) oder ‘Hessian Ministry of Higher Education, Research and the Arts’ funding reference number: III L 4- 518/17.004 (2010)).

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Authors and Affiliations

  1. Division of Allergy, Department for Children and Adolescents, Pulmonology, and Cystic Fibrosis, Children's Hospital, Goethe University, Frankfurt, Germany

    J Pietzner, B M Merscher, R P Duecker, O Eickmeier, D Fußbroich, S Zielen & R Schubert

  2. Department of Internal Medicine, Division of Nephrology, Goethe University, Frankfurt, Germany

    P C Baer

  3. Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents, Goethe University, Frankfurt, Germany

    P Bader

  4. Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe University, Frankfurt, Germany

    D Del Turco

  5. Institute of Transfusion Medicine and Immune Hematology, Blood Donation Service of the German Red Cross, Goethe University, Frankfurt, Germany

    R Henschler

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Pietzner, J., Merscher, B., Baer, P. et al. Low-dose irradiation prior to bone marrow transplantation results in ATM activation and increased lethality in Atm-deficient mice. Bone Marrow Transplant 51, 560–567 (2016). https://doi.org/10.1038/bmt.2015.334

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